1. Field of the Invention
This invention relates to novel pyrrolidinone derivatives and also to antipsychotics and ischemic cerebral disease therapeutics containing the derivatives.
2. Description of the Related Art
Schizophrenia occurs at a high rate of one out of every 130 persons and is often developed in adolescence. If a patient is left without adequate treatment, his or her personality progressively deteriorates, resulting in total decay of his or her self-developing functions. Schizophrenia is therefore a serious social problem. As a cause for this disease, certain dopamine dysfunction in the brain has been indicated. The effectiveness of dopamine antagonists such as chlorpromazine and haloperidol as antipsychotics is considered to support the above indication. However, dopamine antagonists are also known to develop at a high rate an extrapyramidal side effect such as acute dystonia, parkinsonism, tardive dyskinesia, thereby presenting another serious problem. In recent years, approaches have been attempted from facets different from the acting mechanisms of conventional drugs. Sigma receptor ligands are considered to be useful for one of such approaches. As "SKF-10047", a sigma receptor agonist, is known to induce psychotic action on men, sigma receptor antagonists are expected to be used as antipsychotics which are not accompanied by extrapyramidal side effects. Rimcazole is known as a drug of this kind, but its affinity and specificity to sigma receptors are still insufficient.
As pyrrolidinone derivatives, compounds represented by the formula (I) are disclosed as herbicides inter alia in U.K. Patent No. 1,522,869 and U.S. Pat. Nos. 4,874,442 and 4,960,457. ##STR2## wherein R.sup.1 represents --Cl, ##STR3## and R.sup.2 represents --CH.sub.2 Cl or --C.sub.2 H.sub.5.
For application as pharmaceutical products, compounds represented by the formula (II) are disclosed in U.K. Patent No. 1,532,055 and are reported to have analgesic properties and antidiarrheal properties. ##STR4## wherein R is selected from the group consisting of H and lower alkyl and benzyl groups; R.sup.1 is selected from the group consisting of H, Cl, Br, F, and trifluoromethyl and lower alkoxy groups; R.sup.2 is selected from the group consisting of H, Cl, Br and F, A is selected from the group consisting of hydroxy, lower alkylcarbonyloxy and lower alkoxycarbonyl groups, and n stands for an integer of 1, 2 or 3.
For application as other pharmaceutical products, compounds represented by the formula (III) were clinically studied as antidemential drugs. They are disclosed in publications led by Butler et al., "Journal of Medicinal Chemistry", 27, 684-691 (1984). ##STR5##
(a) X: H; R: --CH.sub.2 CONH.sub.2 (piracetam)
(b) X: OH; R: --CH.sub.2 CONH.sub.2 (oxiracetam)
(c) X: H; R: --CH.sub.2 CONH(CH.sub.2)2N[CH(CH.sub.3).sub.2 ].sub.2
(d) X: H; R: ##STR6## (aniracetam)
Compounds, which have a structure equivalent to that represented by the following formula (IV): ##STR7## wherein X generally represents a substituted or unsubstituted C.sub.2-4 alkylene group, Y represents a carbonyl or methylene group, A represents a linking moiety such as an alkylene, alkanoyl or alkyleneamidoalkylene group, W represents a nitrogen atom, and B represents a group having a pyrimidinyl, pyridinyl or benzoisothiazolyl ring, are reported to have antipsychotic, anxiolytic, antiemetic, cognition-enhancing and antidemential activities. They are disclosed in U.S. Pat. Nos. 4,668,687, 3,717,634, 4,423,049 and 4,524,206.
Compounds, which are represented by the following formula (V): ##STR8## wherein X represents a hydrogen or chlorine atom, are described as exhibiting analgesic properties and at the same time, weak antiinflammatory action in Malawska et al., "Synthesis and Pharmacological Properties of Some 2-Pyrrolidinone Mannich Bases", Polish Journal of Pharmacology, 34, 373-382 (1982). Further, U.S. Pat. No. 4,826,843 to Mattson et al. discloses that compounds of the following formula (VI) have activities to enhance cognition and memory: ##STR9## wherein X represents an ethylene chain or a 1,2-benzo ring, Y represents a carbonyl (only when X is a 1,2-benzo ring) or methylene group, R.sup.1 represents a hydrogen atom or a lower alkyl group, and Z represents a R.sup.2,R.sup.3 -disubstituted diazinyl ring selected from pyridazine, pyrimidine and pyrazine rings with R.sup.2 and R.sup.3 being independently chosen from hydrogen, lower (C.sub.1-4) alkyl, lower alkoxy, lower alkylthio, cyano, trifluoromethyl, pentafluoroethyl and halogen.
Further, U.S. Pat. No. 4,767,759 discloses that compounds represented by the following formula (VII) have antidemential activities: ##STR10## wherein R.sup.1 represents a hydrogen atom or a methyl group, R.sup.2 represents a pyridyl or phenyl group or a mono or di-substituted phenyl group in which each substituent is a C.sub.1-2 alkoxy group, fluorine atom, chlorine atom, bromine atom, trifluoromethyl group or C.sub.1-4 alkyl group, R.sup.3 and R.sup.4 may be the same or different and represent a hydrogen atom or a C.sub.1-2 alkyl group or the two groups of R.sup.3 and R.sup.4 may be coupled together with a nitrogen atom to form a saturated, 5- or 6-membered ring, which may contain O or N as another hetero atom or may have been substituted by methyl groups, or an imidazole ring, and the aminoalkyl group is located at the 4- or 5-position.
In addition, compounds represented by the following formula (VIII): ##STR11## wherein R.sup.1 represents CH.sub.3 or H and R.sup.2 represents CH.sub.3 were studied as monoamine oxidase B inhibitors by Silverman et al. [see "Journal of Medicinal Chemistry" 36, 3606-3610 (1993)].
None of the above compounds are however described to have high affinity to sigma receptors and to exhibit antipsychotic action.